tcsc7406 YM158 (free base)

YM158 free base is a potent and selective LTD₄ and TXA₂ receptor antagonist with pA₂ values of about 8.87 and 8.81, respectively.

IC50 & Target: pA2: 8.87 (LTD₄ receptor)^[1]


pA2: 8.81 (TXA₂ receptor)^[1]

In Vitro: YM158 antagonizes leukotriene (LT) D₄ and thromboxane (TX) A₂ receptors. Functional assays in vitro show that YM158 exhibits competitive dual antagonism of LTD₄ and TXA₂ receptor-mediated contraction of isolated guinea pig tracheae, with pA₂ values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD₄ receptor is approximately 6.5 times less potent than that of Montelukast, and that for the TXA₂ receptor is 2.5 times more potent than that of Seratrodast. YM158 also inhibits PGD₂- and PGF_2α -induced tracheal contractions. YM158 antagonizes the stable TXA₂ analog U46619-induced aggregation of both guinea pig and human platelets and inhibits the LTD₄-induced contraction of guinea pig ileum. YM158 produces a concentration-dependent inhibition of guinea pig ileum contraction induced by 1 nM LTD₄ with an IC₅₀ value of 0.58 nM^[1].

In Vivo: YM158, an orally active dual antagonist for LTD₄ and TXA₂ receptors, is expected to have a stronger antiasthmatic efficacy in a broader class of asthmatic patients than single antagonistic drugs.The effect of YM158 is examined on these asthmatic responses in mediator-controlled and passively sensitized guinea pigs. Because the inhibitory effects of YM158 on increase in the airway resistance induced by LTD₄ or U46619 are shown to be dose-dependent when p.o. administered 1 h before LTD₄ or U46619 injection, with ED₅₀ values of 8.6 and 14 mg/kg, respectively, the antagonistic activities of p.o. YM158 for LTD₄ and TXA₂ receptors are exhibited at the same dose range. Oral YM158 shows significant effects, approximately the same as the combination of Pranlukast and Daltroban on antigen-induced response under various conditions; namely, where LTD₄ is predominant, TXA₂ is predominant; or where both mediators participated equally. In groups not treated with Indomethacin, administration of Daltroban (10 mg/kg), a combination of Pranlukast (30 mg/kg) and Daltroban (10 mg/kg), or YM158 (30 mg/kg) significantly prolongs the onset time for asthmatic response and significantly suppresses symptoms^[2].